1. Field of the Invention
The present invention is directed to compounds useful for treatment of poisoning by bacillus anthracis (anthrax infection or poisoning). More particularly, the invention is directed to compounds capable of inhibiting the lethal effects of infection by anthrax bacteria and are useful in the treatment of poisoning by anthrax. The compounds of the invention are hydroxamic acid derivatives of phenoxy-acetic acid and its thio, and related analogs.
2. Background Art
Anthrax is a disease caused by infection of mammals, including humans, by bacillus anthracis. Spores of these bacteria can enter the mammalian, including human body, through skin abrasions, the digestive system or inhalation. Whereas anthrax poisoning in humans through skin abrasion or the digestive system can often be treated with antibiotics, anthrax poisoning in humans by ingestion of aerosol usually results in death of the infected individual.
Relatively recently, devices have been made which incorporate bacillus anthracis or its spores and are capable of releasing the bacteria or its spores in aerosol form. This “weaponized” form of anthrax can serve as a “weapon of mass destruction” in biological warfare and is feared in the Western World for its potential use by terrorists against civilian populations.
For all these reasons a serious effort has been made in the fields of medical and related biological research to elucidate the mode and agent of poisoning by bacillus anthracis and efforts have been made to synthesize compounds which act as inhibitors of the lethal toxins and therefore can treat the infection.
The following scientific publications describe or relate to the manner of infection by the bacteria and to elucidation of the toxic factors and their mode of action in the mammalian, including human body: Dixon et al. (1999) N. England J. Med. 341. 815-26; Mock et al. Annu. Rev. Microbiol. 55. 647-71; Vitalae et al. (1998) Biochem. Biopphys. Res. Commun. 248, 706-11; Vitalae et al. (2000) Biochem J. 352 Pt 3, 739-45; Duesbery et al. (1998) Science 280. 734-7; Duesbery et al. International Publication No. WO 99/50439; Hammond et al. (1998) Infect. Immun. 66, 2374-8. A summary of these findings is that the toxin, called “lethal factor”, released by bacillus anthraci is an enzyme that splits an essential peptide needed by mammalian organisms for signal transmission. Thus, inhibitors of this bacterial enzyme are candidates for drugs for treatment of anthrax poisoning.
Published US Patent Application No. 2005/0148629 (Jul. 7, 2005) describes hydroxamic acid compounds which have the general formula shown below
where the R1 is aryl, or heteroaryl, or heterocyclic and where R represents a large number of potential substituents, including alkyl, and which can be used in the treatment of anthrax poisoning.
Published International Application WO 2005/027856 (Mar. 31, 2005) describe numerous compounds said to be inhibitors of anthrax lethal factor.
Published International Application WO 97/24117 discloses compounds of the general formula

including some examples where the variable p=1, q=0 and m=1. Said compounds are said to be inhibitors of cyclic AMP phosphodiesterase.
Published European Patent Application EP 1 707 560 A1 includes formulas 1 through 10 (pages 1-15) which purport to cover a very large number of compounds of diverging structures, some of which are pertinent to the compounds of the present invention.
The present invention represents a further advance in the field by providing hydroxamic acid derivatives of phenoxyacetic acid and analogs which are useful to treat anthrax poisoning.